J. Pharm. Pharmacogn. Res., vol. 13, no. 3, pp. 919-924, May-Jun 2025.

DOI: https://doi.org/10.56499/jppres24.2069_13.3.919

Original Article

Extract of Holothuria scabra exhibits synergistic effect with chemotherapeutic agents against breast cancer in vitro

[Extracto de Holothuria scabra muestra un efecto sinérgico con agentes quimioterapéuticos contra el cáncer de mama in vitro]

Teresa Liliana Wargasetia^1*, Laella Kinghua Liana¹, Nashi Widodo², Yuslinda Annisa², Feri Eko Hermanto³

¹Faculty of Medicine, Universitas Kristen Maranatha (Maranatha Christian University), Bandung, Indonesia.

²Biology Department, Faculty of Mathematics and Natural Sciences, University of Brawijaya, Malang, Indonesia.

³Faculty of Animal Sciences, Brawijaya University, Malang, Indonesia.

*E-mail: teresa.lw@med.maranatha.edu

Abstract

Context: Sea cucumbers have been identified as highly potential contenders in the fight against breast cancer.

Aims: To investigate the potential of Holothuria scabra extract for anticancer against breast cancer cells in vitro by investigating its synergistic effects when integrated with frequently used chemotherapeutic medications.

Methods: The Combenefit software was employed to assess the human breast cancer cell line T47D viability towards a synergistic combination of H. scabra extract and chemotherapeutic medications (cisplatin, doxorubicin, and neratinib). The investigation encompassed assessing the combination by utilizing a cell viability experiment employing a water-soluble tetrazolium-1 reagent. Subsequently, the selective cytotoxic effect was assessed by subjecting the highest cytotoxicity score to TIG-1-20 normal cells.

Results: The synergistic model was evaluated by comparing interaction analysis through Loewe, Bliss, and Highest Single Agent (HSA) models. Combinations of H. scabra and Cisplatin showed synergistic activity with similar T47D cell viability values. However, the Loewe synergistic model had a higher T47D cell viability value, while the combination of H. scabra and neratinib had a higher T47D cell viability value. Moreover, co-administration of H. scabra and doxorubicin demonstrated notable efficacy in inhibiting the proliferation of T47D cells while exhibiting no cytotoxic effects on TIG-1-20 cells.

Conclusions: Concurrent administration of H. scabra extract and doxorubicin exhibits promising synergistic properties in inhibiting the proliferation of T47D breast cancer cells while demonstrating no toxicity towards TIG-1-20 normal cells.

Keywords: chemotherapy; complementary medicine; natural products; sea cucumbers.

Resumen

Contexto: Los pepinos de mar han sido identificados como contendientes de alto potencial en la lucha contra el cáncer de mama.

Objetivos: Investigar el potencial del extracto de Holothuria scabra como anticancerígeno contra las células de cáncer de mama in vitro mediante la investigación de sus efectos sinérgicos cuando se integra con medicamentos quimioterapéuticos de uso frecuente.

Métodos: Se empleó el software Combenefit para evaluar la viabilidad de la línea celular de cáncer de mama humano T47D frente a una combinación sinérgica de extracto de H. scabra y medicamentos quimioterapéuticos (cisplatino, doxorrubicina y neratinib). La investigación abarcó la evaluación de la combinación mediante la utilización de un experimento de viabilidad celular empleando reactivo tetrazolio-1 soluble en agua. Posteriormente, se evaluó el efecto citotóxico selectivo sometiendo la puntuación más alta de citotoxicidad a células normales TIG-1-20.

Resultados: El modelo sinérgico se evaluó comparando el análisis de interacción a través de los modelos Loewe, Bliss y Highest Single Agent (HSA). Las combinaciones de H. scabra y cisplatino mostraron una actividad sinérgica con valores similares de viabilidad celular T47D. Sin embargo, el modelo sinérgico de Loewe tuvo un valor de viabilidad celular T47D más alto, mientras que la combinación de H. scabra y neratinib tuvo un valor de viabilidad celular T47D más alto. Además, la administración conjunta de H. scabra y doxorrubicina demostró una eficacia notable en la inhibición de la proliferación de células T47D, sin exhibir efectos citotóxicos sobre las células TIG-1-20.

Conclusiones: La administración simultánea de extracto de H. scabra y doxorrubicina exhibe prometedoras propiedades sinérgicas en la inhibición de la proliferación de células de cáncer de mama T47D, sin demostrar toxicidad hacia las células normales TIG-1-20.

Palabras Clave: medicina complementaria; pepinos de mar; productos naturales; quimioterapia.

 

https://jppres.com/jppres/pdf/vol13/jppres24.2069_13.3.919.pdf

Citation Format: Wargasetia TL, Liana LK, Widodo N, Annisa Y, Hermanto FE (2025) Extract of Holothuria scabra exhibits synergistic effect with chemotherapeutic agents against breast cancer in vitro. J Pharm Pharmacogn Res 13(3): 919–924. https://doi.org/10.56499/jppres24.2069_13.3.919

References

Caesar LK, Cech NB (2019) Synergy and antagonism in natural product extracts: When 1 + 1 does not equal 2. Nat Prod Rep 36: 869–888. https://doi.org/10.1039/c9np00011a

Chan WJ, Adiwidjaja J, McLachlan AJ, Boddy AV, Harnett JE (2023) Interactions between natural products and cancer treatments: Underlying mechanisms and clinical importance. Cancer Chemother Pharmacol 91(2): 103–119. https://doi.org/10.1007/s00280-023-04504-z

De Sanctis R, Jacobs F, Benvenuti C, Gaudio M, Franceschini R, Tancredi R, Pedrazzoli P, Santoro A, Zambelli A (2022) From seaside to bedside: Current evidence and future perspectives in the treatment of breast cancer using marine compounds. Front Pharmacol 13: 909566. https://doi.org/10.3389/fphar.2022.909566

Di Veroli GY, Fornari C, Wang D, Mollard S, Bramhall JL, Richards FM, Jodrell DI (2016) Combenefit: An interactive platform for the analysis and visualization of drug combinations. Bioinform 32(18): 2866–2868. https://doi.org/10.1093/bioinformatics/btw230

Huang M, Lu J, Ding J (2021) Natural products in cancer therapy: Past, present and future. Nat Prod Bioprospect 11: 5–13. https://doi.org/10.1007/s13659-020-00293-7

Kan LL-Y, Chan BC-L, Leung P-C, Wong C-K (2023) Natural-product-derived adjunctive treatments to conventional therapy and their immunoregulatory activities in triple-negative breast cancer. Molecules 28(15): 5804. https://doi.org/10.3390/molecules28155804

Kumar NB (2021) The promise of nutrient-derived bioactive compounds and dietary components to ameliorate symptoms of chemotherapy-related cognitive impairment in breast cancer survivors. Curr Treat Options Oncol 22: 67. https://doi.org/10.1007/s11864-021-00865-w

Mann J (2002) Natural products in cancer chemotherapy: Past, present and future. Nat Rev Cancer 2: 143–148. https://doi.org/10.1038/nrc723

Mitra S, Dash R (2018) Natural products for the management and prevention of breast cancer. Evid Based Complement Altern Med 2018: 8324696. https://doi.org/10.1155/2018/8324696

Naja F, Fadel RA, Alameddine M, Aridi Y, Zarif A, Hariri D, Mugharbel A, Khalil M, Nahleh Z, Tfayli A (2015) Complementary and alternative medicine use and its association with quality of life among Lebanese breast cancer patients: A cross-sectional study. BMC Complement Altern Med 15: 444. https://doi.org/10.1186/s12906-015-0969-9

Pichot CS, Hartig SM, Xia L, Arvanitis C, Monisvais D, Lee FY, Frost JA, Corey SJ (2009) Dasatinib synergizes with doxorubicin to block growth, migration, and invasion of breast cancer cells. Br J Cancer 101: 38–47. https://doi.org/10.1038/sj.bjc.6605101

Pranoto D, Ratnawati H, Wargasetia TL, Octavallen A, Rachmat MAA (2023) Sea cucumber reduces breast cancer tumor size through inhibition of MMP9 dependent HER2 expression in breast cancer mice model. Trop J Nat Prod Res 7(9): 4010–4015. https://tjnpr.org/index.php/home/article/view/2652

Purcell SW, Lovatelli A, González-Wangüemert M, Solís-Marín FA, Samyn Y, Conand C (2012) Commercially important sea cucumbers of the world. Rome: Food and Agriculture Organization of the United Nations, 256 p. https://openknowledge.fao.org/handle/20.500.14283/cc5230en

Stöcker A, Mehnert-Theuerkauf A, Hinz A, Ernst J (2023) Utilization of complementary and alternative medicine (CAM) by women with breast cancer or gynecological cancer. PloS One 18(5): e0285718. https://doi.org/10.1371/journal.pone.0285718

Wargasetia TL, Ratnawati H, Liana LK, Larissa L, Imannuel EV (2024) Holothuria scabra extract improves histopathological features and inhibits cancer growth through IL-6 and NF-κB signaling pathways in breast cancer mice model. Res J Pharmacogn 11(2): 1–9. https://doi.org/10.22127/rjp.2023.417833.2233

Wargasetia TL, Ratnawati H, Widodo N (2022) Sea cucumber compounds targeting NF-κB in cancer treatment. Bioinform Biol Insights 16: 11779322221091740. https://doi.org/10.1177/11779322221091740

Wargasetia TL, Ratnawati H, Widodo N, Widyananda MH (2023) Antioxidant and anti-inflammatory activity of sea cucumber (Holothuria scabra) active compounds against KEAP1 and iNOS protein. Bioinform Biol Insights 17: 11779322221149613. https://doi.org/10.1177/11779322221149613

Wargasetia TL, Widodo (2017) Mechanisms of cancer cell killing by sea cucumber-derived compounds. Invest New Drugs 35: 820–826. https://doi.org/10.1007/s10637-017-0505-5

Wargasetia TL, Widodo N (2018) Methanol extract of Holothuria scabra inhibits cell growth and induces apoptosis in T47D breast cancer cells. ESMO Open 3(suppl. 2): A182–A183. https://doi.org/10.1136/esmoopen-2018-EACR25.434

Widodo N, Puspitarini S, Widyananda MH, Alamsyah A, Wicaksono ST, Masruri M, Jatmiko YD (2022) Anti-cancer activity of Caesalpinia sappan by downregulating mitochondrial genes in A549 lung cancer cell line. F1000Res 11: 169. https://doi.org/10.12688/f1000research.76187.2

Yen C, Zhao F, Yu Z, Zhu X, Li CG (2022) Interactions between natural products and tamoxifen in breast cancer: A comprehensive literature review. Front Pharmacol 13: 847113. https://doi.org/10.3389/fphar.2022.847113

© 2025 Journal of Pharmacy & Pharmacognosy Research